Dear all,
I am trying to conjugate amino groups of chitosan with methacrylic anhydride. I am trying to understand chemistry of the reaction. Here is the mechanism:
https://chem.libretexts.org/Core/Organic_Chemistry/Anhydrides/Reactivity_of_Anhydrides/Acid_Anhydrides_React_with_Amines_to_Form_Amides
As you see, reaction starts with nucleophilic attack of amines and so on. Here is my question:
Let's consider I have chitosan (pKa: 6.5) solution in pH 3.5. In this pH, most of the amino groups, maybe 99.9% of them are protonated. So, there are much less number of nucleophilic amine groups which makes the reaction harder. Would you expect this reaction happen? It was reported in the literature that it is possible and I am curious about the possible reasons. Do you have any idea? I will be waiting for your answers.
Thank you all.
Best,
Good question.
Consider the structure of chitosan. In each repeating unit, there are (2 O, 2 OH, and one NH2) and the 5 sites are susceptible to protonation. The pH of 3.5 is not that low for protonating all & the entangled polymeric chains will not allow this (Remember that the pH of gastric acid is 1.5 to 3.5 in the human stomach !).
I looked well at the mechanism & I think it is convincing. It is well-known that an acid anhydride reacts with an amine to give an amide & those who propose mechanisms try to interpret how this occurs in a logical way.
My expectation is that your reaction will happen BUT the yield may be low & the degree of conversion may not be high, as we like.
I think the reaction will occur to some extent because not every amine will be protonated and the equilibrium is dynamic but it will be slow and may stop at a low conversion rate. Maybe DMAP can act as a catalyst. Is pH 3.5 necessary? An increase of pH to 5-6 by the addition of pyridine (which can also act as an catalyst) will give better results, probably.
Hi Uğur, if this in an industrial setting, chitosan will be almost insoluble at pH 3.5. Therefore, raise the pH to 7.0 with phosphate buffers to make the chitosan more soluble and use excess acetic anhydride to make the chitosan amide bonds.
If this is an academic exercise, then I'm afraid I cant be of much help.
As stated by others, the reaction can occur since the equilibrium is dynamic and the polyelectrolyte character of chitosan reduces the basic character of amines that neighbor protonated amines. As to the efficiency... what are your goals?
Why are you trying to make methacrylated chitosan? Do you need conversion approaching 100%? If not, will 50% work for your purpose?
Why are you using methacrylic anhydride? This is a very wasteful reagent for this reaction (for each amide formation you also make a methacrylic acid - which might then form an ion pair with the free amines of the chitosan) - methacryloyl chloride would seem a better choice: more reactive, less expensive, the salt that will form with the free amines will be HCl instead of a polymerizable acid.... Or you could just use methacrylic acid and some coupling agents (DMAP and a water soluble carbodiimide). This might work as well and is a much milder approach.
The pH of your reaction is irrelevant due, as pointed before, to the equilibrium, and the keto protonated product will be activated . Since you are forming a weaker base and acid the reaction will happens.
As Nitrogen in the amine group and O in the acid anhydride both have the ability to protonate but in this case nitrogen is less convenient toward protonation due to the less stable structure that form after the protonation but O can be frequently protonated due to the resonance structure in the acid anhydride molecule. This is the reason that not all molecule of amine protonate
@Americo. Have you ever tried to dissolve chitosan particles at pH 3.5?
They won't dissolve because of the protonated amino groups. Chitosan at pH 3.5 forms clumps that are inaccessible to the solvent.
@Steingrimur. I was not talking about chitosan but at a general reaction. Ugur just said he wanted to understand the general reaction mechanism and its pH dependence. Of course if compounds are not soluble or miscible it will be difficult the reaction occur.
@Americo, thanks for the explanation.
Like I said previously, I am not an expert at academic discussions of reaction mechanisms. I only how to do them efficiently in an industrial setting.
This article:
Sarala Naik, Gitalee Bhattacharjya, Veerababu Rao Kavala, and Bhisma K. Patel. Mild and eco-friendly chemoselective acylation of amines in aqueous medium. ARKIVOC 2004 (i) 55-63
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